Lead. For decades, sleep disturbances in Alzheimer’s disease have been blamed on amyloid plaques, the sticky protein clumps that accumulate between neurons. A study published July 20 in Alzheimer’s & Dementia turns that assumption on its head. Researchers at the University of Kentucky show that the real culprit is not the plaques themselves but the brain’s overactive immune cells, called microglia. By temporarily removing most of these cells from Alzheimer’s model mice, the scientists restored more than two hours of sleep per day, without touching a single plaque.
The finding reframes the biology of Alzheimer’s-related sleep loss and opens the door to treatments that calm immune activity rather than clearing amyloid.
The microglia connection. Microglia are the brain’s resident immune cells. They patrol for damage, infection, and debris. When amyloid plaques begin to form early in the disease, microglia swarm to the site and mount an inflammatory response. That response, the new study shows, is what steals sleep.
“We found that microglia are immune cells that, when they respond to plaques, kick off this elaborate cascade of inflammation, as if the microglia are partying all night, and keeping the brain awake,” said lead researcher Shannon L. Macauley, PhD, of the University of Kentucky.
The team used a drug called PLX3397 (Pexidartinib) to temporarily eliminate about 87 percent of microglia from mice engineered to develop Alzheimer’s pathology. With most microglia gone, the mice regained more than two hours of sleep each day, a striking gain in an animal that typically sleeps only 12 to 14 hours total. The effect held despite amyloid plaques remaining at the same levels.
To measure sleep, the researchers used electroencephalography (EEG) and electromyography (EMG) recordings, the gold standard for distinguishing sleep stages. They tracked the mice at two ages: 6 months, when plaques first appear, and 18 months, when pathology is advanced. Light sheet microscopy gave them three-dimensional views of the brain’s immune landscape alongside the sleep data.
The ceiling effect. One surprising result emerged when the team compared early-stage and advanced-stage mice. The sleep loss kicked in as soon as plaques began forming and the microglial response took hold. Adding more plaques later did not make the sleep loss worse. The researchers call this a “ceiling effect”, the inflammatory response reaches a maximum early in the disease, then plateaus.
This matters because it suggests that the window for intervention may be wider than expected. Even patients with advanced Alzheimer’s could potentially benefit from therapies that calm microglial activity rather than remove plaques. The microglial response is already maxed out; targeting it directly could restore sleep regardless of how much amyloid has accumulated.
The study also clarified how Alzheimer’s disrupts sleep differently than normal aging. In the Alzheimer’s mice, the pathology specifically reduced NREM (non-rapid eye movement) sleep, the deep, restorative stage that helps the brain consolidate memories and clear metabolic waste. Normal aging, by contrast, primarily reduced REM sleep. This distinction could help clinicians distinguish age-related insomnia from Alzheimer’s-driven sleep loss.
Why it matters. Sleep disruption is one of the earliest and most distressing symptoms of Alzheimer’s disease. It often appears years before memory loss becomes obvious, and it places a heavy burden on caregivers. If microglial inflammation is the driver, then portable EEG devices could serve as an early screening tool, picking up signature NREM sleep changes before cognitive decline sets in.
Therapeutically, the results point away from anti-amyloid drugs and toward anti-inflammatory strategies. Macauley’s team is already planning to test two existing drugs that might calm microglial overactivity: metformin, a common diabetes medication, and stiripentol, an antiseizure drug. Both are already approved for other conditions, which could accelerate their path into Alzheimer’s trials.
“We are really excited about these drug trials because they are currently FDA-approved drugs that could be repurposed for Alzheimer’s disease,” Macauley said.
Limits. The study was conducted in mice, not humans, and the drug used to remove microglia (PLX3397) is too blunt an instrument for clinical use, it eliminates nearly all microglia rather than merely calming them. Long-term microglial depletion could leave the brain vulnerable to infection or injury. The next step is finding ways to modulate microglial activity without wiping them out, which is why the team is turning to repurposed drugs with milder effects.
Bottom line. Alzheimer’s disease robs patients of deep, restorative sleep through an inflammatory immune response, not through amyloid plaques themselves. Calming the brain’s microglia can restore that lost sleep even when plaques remain in place. The finding uncouples amyloid from sleep loss and suggests that anti-inflammatory approaches, some using drugs already on the market, may offer a faster path to treating one of Alzheimer’s most debilitating symptoms.
Source. Constantino NJ, et al. “Microglial depletion ameliorates Alzheimer’s disease-associated sleep loss without altering amyloid burden.” Alzheimer’s & Dementia, July 20, 2026. DOI: 10.1002/alz.71579. Funding: NIH R01AG068330, R01AG093847; Cure Alzheimer’s Fund ($287,236).